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Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling
Ajay Dixit, … , Rolf A. Brekken, Paolo P. Provenzano
Ajay Dixit, … , Rolf A. Brekken, Paolo P. Provenzano
Published October 18, 2022
Citation Information: JCI Insight. 2022;7(22):e153242. https://doi.org/10.1172/jci.insight.153242.
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Research Article Oncology

Targeting TNF-α–producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling

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Abstract

Pancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely owing to robustly fibrotic and immunosuppressive tumor microenvironments. It has been postulated that excessive accumulation of immunosuppressive myeloid cells influences immunotherapy resistance, and recent studies targeting macrophages in combination with checkpoint blockade have demonstrated promising preclinical results. Yet our understanding of tumor-associated macrophage (TAM) function, complexity, and diversity in PDA remains limited. Our analysis reveals significant macrophage heterogeneity, with bone marrow–derived monocytes serving as the primary source for immunosuppressive TAMs. These cells also serve as a primary source of TNF-α, which suppresses expression of the alarmin IL-33 in carcinoma cells. Deletion of Ccr2 in genetically engineered mice decreased monocyte recruitment, resulting in profoundly decreased TNF-α and increased IL-33 expression, decreased metastasis, and increased survival. Moreover, intervention studies targeting CCR2 with a new orthosteric inhibitor (CCX598) rendered PDA susceptible to checkpoint blockade, resulting in reduced metastatic burden and increased survival. Our data indicate that this shift in antitumor immunity is influenced by increased levels of IL-33, which increases dendritic cell and cytotoxic T cell activity. These data demonstrate that interventions to disrupt infiltration of immunosuppressive macrophages, or their signaling, have the potential to overcome barriers to effective immunotherapeutics for PDA.

Authors

Ajay Dixit, Aaron Sarver, Jon Zettervall, Huocong Huang, Kexin Zheng, Rolf A. Brekken, Paolo P. Provenzano

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Figure 1

Human PDA has heterogeneous macrophage populations.

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Human PDA has heterogeneous macrophage populations.
(A) TCGA data set an...
(A) TCGA data set analysis demonstrating that transcripts identifying myeloid cells and TAMs in PDA (i.e., CD68, CD11b, and CD14) are overexpressed in PDA. *P < 0.0001. (B) Transcripts associated with CD68+ macrophages correlate with poor prognosis in PDA patients (TCGA data set analysis). TPM, transcripts per million. (C) Distribution of factors that regulate macrophage polarization and function within the heterogeneous macrophage populations in PDA showing the strongest signal for immunosuppressive factors. (D and E) Gene Ontology pathway analysis of human PDA CD68+ macrophages showing decreased antitumor immune activation (i.e., immunosuppressive behavior) (D) and increased pathways enriched in TNF-α production (E).

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